Effects of the new A2 adenosine receptor antagonist 8FB‐PTP, an 8 substituted pyrazolo‐triazolo‐pyrimidine, on in vitro functional models

Abstract

1 We have characterized the in vitro pharmacological profile of putative A₂ adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (8FB-PTP) and 5-amino-9-chloro-2-(2-furyl 1,2,4-triazolo [1,5-c] quinazoline (CGS 15943), and the xanthine derivative (E)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropyl-xanthine (KF 17837). 2 In binding studies on bovine brain, 8FB-PTP was the most potent (K_i = 0.074 nm) and selective (28 fold) drug on A₂ receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. 3 In functional studies, 8FB-PTP antagonized 5′-N-ethyl-carboxamidoadenosine (NECA)-induced vasorelaxation of bovine coronary artery (pA₂ = 7.98) and NECA-induced inhibition of rabbit platelet aggregation (pA₂ = 8.20). CGS 15943 snowed weak activity in the platelet aggregation model (pA₂ = 7.43) and failed to antagonize NECA-induced vasodilatation. KF 17837 was ineffective in both models up to micromolar concentrations. 4 Antagonism of A₁-mediated responses was tested versus 2-chloro-N⁶-cyclopentyladenosine (CCPA) in rat atria. 8FB-PTP and CGS 15943 also antagonized competitively the negative chronotropic response induced by CCPA. Conversely, KF 17837 was unable to reverse A₁-mediated responses. 5 8FB-PTP is a potent and competitive antagonist of responses mediated by A₂ adenosine receptors. The data provided a basis to reduce, by further chemical modifications, the affinity at A₁ receptor and therefore enhance A₂ receptor selectivity.